Therapeutic Role of Bmi-1 Inhibitors in Eliminating Prostate Tumor Stem Cells
Abstract
Current prostate cancer (PCa) management calls for identifying novel and more effective therapeutic approaches that could target therapy resistant self-renewing prostate tumor-initiating cells (TICs). Our focus is on BMI-1 (B-cell-specific MMLV insertion site-1), a protein that regulates stem cell self-renewal. During the first two years of this award and in collaboration with the initiating and other partnering PIs, we have developed and optimized a time-of-adherence assay to identify TICs that we demonstrated to have CD49bhiCD29hiCD44hi cell phenotype. This year, we examined the first known translational inhibitors of BMI-1; C-209 to target prostate TICs alone and in combination with taxotere, the standard of care. Employment of this specific BMI-1 inhibitor on patient-derived cells significantly decreased spheroid formation in vitro and prevented tumor initiation in vivo in mice (Bertino Lab), thereby diminishing the frequency of TICs from a large number of patients tissues. Furthermore, C-209 induced cell senescence, G1 cell cycle arrest, and reduced intratumor BMI-1 levels, while displaying antitumor activity in mouse xenografts did not exert toxic effects on normal tissues. BMI-1 targeted therapy when combined with taxotere resulted in further antitumor activities. Therefore, we have accomplished our third year s goal to demonstrate the beneficial effects of targeting prostate TICs in vivo in mice in this synergistic award between three laboratories (Sabaawy, Bertino, and Kim) to develop a therapeutic strategy for BMI-1 inhibitors in prostate cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2015
- Accession Number
- ADA624243
Entities
People
- Hatem E Sabaawy
- Isaac Kim
- Joseph Bertino
Organizations
- Rutgers University–New Brunswick